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J. Biol. Chem., Vol. 277, Issue 36, 32417-32420, September 6, 2002

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ACCELERATED PUBLICATION
The Drosophila melanogaster brainiac Protein Is a Glycolipid-specific 1,3N-Acetylglucosaminyltransferase^*

Reto Müller, Friedrich Altmann, Dapeng Zhou^§, and Thierry Hennet^¶

From the Institute of Physiology, University of Zürich, Winterthurerstrasse 190, 8057 Zürich, Switzerland and the  Institute of Chemistry, Universität für Bodenkultur, Muthgasse 18, A-1190 Wien, Austria

Received for publication, June 26, 2002

	ABSTRACT

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Mutations at the Drosophila melanogaster brainiac locus lead to defective formation of the follicular epithelium during oogenesis and to neural hyperplasia. The brainiac gene encodes a type II transmembrane protein structurally similar to mammalian 1,3-glycosyltransferases. We have cloned the brainiac gene from D. melanogaster genomic DNA and expressed it as a FLAG-tagged recombinant protein in Sf9 insect cells. Glycosyltransferase assays showed that brainiac is capable of transferring N-acetylglucosamine (GlcNAc) to -linked mannose (Man), with a marked preference for the disaccharide Man(1,4)Glc, the core of arthro-series glycolipids. The activity of brainiac toward arthro-series glycolipids was confirmed by showing that the enzyme efficiently utilized glycolipids from insects as acceptors whereas it did not with glycolipids from mammalian cells. Methylation analysis of the brainiac reaction product revealed a 1,3 linkage between GlcNAc and Man, proving that brainiac is a 1,3GlcNAc-transferase. Human 1,3GlcNAc-transferases structurally related to brainiac were unable to transfer GlcNAc to Man(1,4)Glc-based acceptor substrates and failed to rescue a homozygous lethal brainiac allele, indicating that these proteins are paralogous and not orthologous to brainiac.

	INTRODUCTION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

The importance of glycoconjugates in regulating developmental processes is continually being supported by studies performed in various model organisms like Caenorhabditis elegans (1), Drosophila melanogaster (2), and the mouse (3). The Drosophila genes sugarless, sulfateless, pipe, tout-velu, and dally participate in the formation of proteoglycans. Loss of function mutations in some of these genes produce polarity phenotypes mechanistically connected to incorrect diffusion of the signaling proteins wingless and hedgehog (4-6). The rotated abdomen locus, whose disruption is associated with a helical rotation of the body, has been found to encode a potential O-mannosyltransferase (7), and fringe, which modulates the interaction of the Notch receptor with its ligands (8), has recently been demonstrated to be a 1,3N-acetylglucosaminyltransferase (GlcNAcT)¹ (9, 10).

The Drosophila gene brainiac (brn) (11) encodes a protein that shares structural motifs with 1,3glycosyltransferases (12, 13). The brn gene is localized on the X chromosome. brn was shown to cooperate with the epidermal growth factor receptor and one of its ligands, the Drosophila TGF homologue gurken (11) during oogenesis. Mutant brn alleles exhibit altered morphology of the follicular epithelium (11), female sterility (14), and germ line loss (15). Furthermore, brn embryos develop neural hyperplasia and epidermal hypoplasia (11) as encountered with Notch hypomorphic alleles and other neurogenic mutants, suggesting implications of brn in Notch signaling (16, 17).

While the relationships between brn and specific signaling pathways have been examined genetically, the nature of these interactions remained elusive as long as the biochemical function of brn was unclear. In the present study, we show that brn has a 1,3N-acetylglucosaminyltransferase (GlcNAcT) activity directed toward the Man(1,4)Glc core structure of arthro-series glycolipids.

	EXPERIMENTAL PROCEDURES

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

Cloning and Expression-- The brn gene was amplified by PCR from D. melanogaster OregonR genomic DNA during 30 cycles at 95 °C for 45 s, 55 °C for 30 s, 72 °C for 60 s using the primers 5'-TTTGGATCCGTCGCCATGCAAAGT-3' and 5'-CCTGTTCTAGATGCTACGCGTAAT-3'. The resulting 1.0-kb fragment was digested with BamHI and XbaI and subcloned into the pFastbac-FLAG(a) vector (Invitrogen) linearized at the BamHI and XbaI sites. The FLAG-tagged brn gene was expressed as a recombinant baculovirus in insect cells as described previously (13). Infected cells (10⁷) were lysed at 72 h post-infection in 600 µl of 50 mM Tris/HCl, pH 7.4, 150 mM NaCl, 1% Triton X-100, and a protein inhibitor mixture (complete, EDTA free, Roche Diagnostics) on ice. Post-nuclear supernatants were incubated with 240 µl of anti-FLAG M2-agarose beads (Sigma) under rotation for 2.5 h at 4 °C. Beads were washed three times with Tris-buffered saline and used as enzyme source for assays.

Glycosyltransferase Assays-- All donor and acceptor substrates were from Sigma except Man(1,4)Glc(1-OpNP) (pNP = p-nitrophenyl), which was purchased from Toronto Research (North York, Canada). Glycosyltransferase activity was assayed for 60 min at 25 °C with 15 µl of beads, 5% Me₂SO, 20 mM MnCl₂, 0.08 mM UDP-GlcNAc including 5 × 10⁴ cpm of UDP-[¹⁴C]GlcNAc (Amersham Biosciences), and various acceptors (see Table I). Reaction products were purified over C₁₈ Sep-Pak cartridges (Waters) (18) and quantified in a Tri-Carb 2900TR liquid scintillation counter (Packard) with luminescence correction.

Glycolipid Extraction-- D. melanogaster Schneider 2 cells, Spodoptera frugiperda Sf9 cells, and human colon carcinoma Caco-2 cells were washed three times in phosphate-buffered saline and extracted in isopropanol:hexane:H₂O (55:25:20). Extracts were spun twice at 500 x g, and supernatants were dried under N₂. Phospholipids were removed by saponification in 0.2 M NaOH in methanol for 24 h at 37 °C. After neutralization with HCl, the extracts were expanded to theoretical upper phase (methanol:water:chloroform, 47:48:3), applied on C₁₈ SepPak cartridges, and eluted with 5 ml of methanol. Eluates were dried under N₂ and resuspended in 500 µl of methanol. The procedure yielded about 120 µg of mannose equivalents for 10⁸ S2 and Sf9 cells and 20 µg of mannose equivalents from 10⁷ Caco-2 cells as determined by the phenol sulfuric acid assay (19).

Thin-layer Chromatography (TLC)-- Glycolipids (5 µg of mannose equivalents per assay) were dried under N₂ and incubated together with 10 µl of beads-bound enzyme in 50 µl of 50 mM cacodylate buffer, pH 7.1, 20 mM MnCl₂, 0.06% Triton X-100, 2.5 × 10⁴ cpm of UDP-[¹⁴C]GlcNAc for 90 min at 25 °C. Reaction products were expanded to theoretical upper phase and purified over C₁₈ Sep-Pak cartridges as described above. After drying over N₂, the eluates were taken up in 100 µl of methanol:chloroform (1:1) and separated on aluminum high-performance thin-layer chromatography plates (Merck, Darmstadt, Germany) using a solvent system of chloroform:methanol:0.25% CaCl₂ (5:4:1). Plates were stained with orcinol sulfuric acid (Sigma). The [¹⁴C]GlcNAc(1,3)Gal(1,4)Glc-ceramide (Lc3) standard was produced enzymatically with the Lc3 synthase 1,3 GlcNacT protein (20) using Gal(1,4)Glc-ceramide (Lc2) (Sigma) as acceptor substrate.

brn Complementation in Drosophila-- Human 3GnT1 (21), 3GnT4 (22) and 3GnT5 (20) cDNAs and the Drosophila brn gene were subcloned into the pUAST vector (23). The rescue constructs pUAST-3GnT1, pUAST-3GnT4, pUAST-3GnT5, and pUAST-brn were injected together with the pUChsp2-3 P-element helper plasmid (Flybase accession FBmc0000938) into yellow white Drosophila embryos using standard procedures. Then, white⁺ progeny was selected and X-chromosomal insertions of the transgene excluded. The GAL4 lines, driving ubiquitous expression of the UAS-transgenes in an armadillo pattern (24), carry Bloomington Stock numbers 1560 and 1561. Males of the genotype yellow white/Y; transgene/+ were mated to virgins forked brn^1.6P6/FM6-w¹; 1560 GAL4/+ and forked brn^1.6P6/FM6-w¹; 1561 GAL4/+ and the progeny examined for males carrying the forked mutation for 8 days after eclosion of the first flies. At least two independent lines of each transgene were used for the complementation assay, which were repeated four times.

Structural Analysis-- A mixture of substrate and of 10 nmol of product was separated by reversed phase HPLC on a 3 × 250 mm column filled with 5 µM ODS Hypersil (Shandon) at a flow rate of 0.6 ml/min. The column was eluted with a linear gradient from 6 to 24% of methanol during 18 min in 0.1 M ammonium acetate, pH 4.0. p-Nitrophenylglycosides were monitored at 245 nm. The mixture was also analyzed after incubation with N-acetyl--hexosaminidase from jack beans (Sigma) (25). The fraction of interest was collected in a screw capped glass vial and dried in a speed-vac concentrator. A small aliquot was used for matrix assisted laser desorption mass spectrometry as described elsewhere (25). The sample was dried over phosphorus pentoxide in vacuo and permethylated using NaOH (26). Partially permethylated alditol acetates were prepared using NaBD₄ as the reducing agent and analyzed by gas chromatography/mass spectrometry using a 60 m SP2330 (Restek) (27) and a Finnigan Ion Trap ITD800. Derivatives of terminal and 3-substituted galactose served to compare retention times with the data given by Doares et al. (27).

	RESULTS

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

We have cloned the D. melanogaster brn gene by PCR amplification and expressed it as an N-terminally FLAG-tagged full-length protein in Sf9 insect cells. The recombinant brn protein was bound to anti-FLAG-agarose beads, and cellular contaminants such as possible endogenous acceptor substrates were washed out before assaying for enzymatic activity. A GlcNAcT activity was only detected toward the Man(1-OpNP) acceptor when monosaccharide substrates were assayed (Table I). Highest activity was measured toward the disaccharide acceptor Man(1,4)Glc(1-OpNP), whereas a slight activity was also detected toward Gal(1,4)Glc(1-OpNP) (Table I). The Man(1,4)Glc structure represents the core of arthro-series glycolipids found in nematodes (28) and insects (29) among others.

In Drosophila, the arthro-series Man(1,4)Glc core is elongated with a 1,3-linked GlcNAc (30), suggesting that brn may represent the enzyme catalyzing this step. To test this hypothesis, we have isolated neutral glycolipids from Drosophila S2 and Spodoptera Sf9 cells and assayed these glycolipids as acceptors for the anti-FLAG beads-bound brn enzyme. A significant GlcNAc-transferase activity was detected when incubating brn together with insect glycolipids, whereas only a low activity was measured with glycolipids extracted from mammalian Caco-2 cells, likely reflecting the low specificity of brn for lactosylceramide. The reaction products were separated by TLC and plates were autoradiographed, revealing a [¹⁴C]GlcNAc-labeled band at the size of a trihexoside ceramide in S2 and Sf9 cells (Fig. 1).

View larger version (114K): [in this window] [in a new window]   Fig. 1.   TLC separation of brn-modified glycolipids. The top panel shows a plate stained with orcinol reagent and the bottom panel the autoradiogram of the same plate. brn-bound beads (brn) or beads preincubated with mock-infected Sf9 cells (mock) were incubated with neutral glycolipids from Drosophila S2 cells (S2), Spodoptera Sf9 cells (Sf9), human Caco-2 cells (Caco), or without added glycolipids (no GL). The neutral glycolipid standard (GL Std) contained: Gal-Cer; Gal(1,4)Glc-Cer (Lc2); Gal(1,4)Gal(1,4)Glc-Cer (Gb3); Gal(1,4)Gal(1,4)Glc-Cer (Gb4), and GalNAc(1,3)GalNAc(1,3)Gal(1,4)Glc-Cer (FS). Lc2/Lc3, Lc2 was elongated to Lc3 by incorporation of [14C] GlcNAc catalyzed by the human 3GnT-V enzyme (20).

The nature of the linkage between GlcNAc and the underlying -linked Man residue was investigated by methylation analysis of the brn reaction product GlcNAc-Man(1-OpNP). In reversed phase HPLC, the presumed disaccharide product eluted slightly ahead of the substrate Man(1-OpNP). The disaccharide peak disappeared upon incubation with N-acetyl--hexosaminidase (Fig. 2A). The purified fraction corresponding to the disaccharide peak exhibited a pseudomolecular ion of m/z 513.5. Linkage analysis of the GlcNAc-Man(1-OpNP) disaccharide product gave a peak at the relative retention time of 0.597, which suggests a 2- or a 3-substituted mannosyl residue (27). The fragment spectrum clearly identified the derivative as substituted in the 3-position (Fig. 2B), thus confirming the identity of brn as a 1,3 GlcNAcT.

View larger version (21K): [in this window] [in a new window]   Fig. 2.   Structural analysis of brn product. A, HPLC separation of product and substrate of 1,3GlcNAcT brn. p-Nitrophenyl--D-mannopyranoside was incubated with brn in the presence of UDP-GlcNAc. The mixture was prepurified over Sep-Pak C18 cartridges and subjected to reversed phase chromatography (trace a). A small product peak (P) eluted ahead of the substrate (S). The product disappeared upon incubation with -N-acetylhexosaminidase (trace b) which indicates it to contain a -linked GlcNAc residue. B, methylation analysis of p-nitrophenyl disaccharide. The electron impact mass spectrum of the partially methylated monodeuterated alditol acetate derived from the mannosyl residue of the disaccharide product shows several fragments indicative of a substitution in position 3 as depicted by the insert. Especially the presence of mass 118 and the absence of mass 190 exclude a 2-substitution, which could not be ruled out from the retention time alone (27).

The brn protein is structurally related to human 1,3 glycosyltransferase enzymes (12, 13). The acceptor specificity of brn for the arthro-series glycolipid core suggested that it represents a paralogous enzyme to the mammalian 1,3 glycosyltransferases, including 1,3 galactosyltransferases (13, 31, 32), 1,3 GlcNAcT (20, 22), and a 1,3-N-acetylgalactosaminyltransferase (33) acting on GlcNAc-, Gal-, and GalNAc-based acceptors. Although no mammalian 1,3 GlcNAcT has been described to act on -linked Man acceptors, we have investigated whether the three human 1,3 GlcNAcT structurally closest to brn can complement the lethal phenotype of brn deficient Drosophila flies. To this end, we have expressed the human 3GnT-I (21), -IV (22), and -V (20) in brn^1.6P6 mutant flies (34) using the UAS-GAL4 transgenesis system (23).

The human 3GnT transgenes and a brn transgene were expressed in flies carrying the allele brn^1.6P6, which causes lethality at the late pupal stage. The transgenes were expressed ubiquitously using armadillo GAL4 transactivator lines. The brn transgene did rescue brn^1.6P6 mutant males from their hemizygous late pupal lethality, whereas the human 3GnT transgenes did not (Table II). The rescue of brn^1.6P6 males was confirmed by detection of the forked marker, whose gene is located besides the brn^1.6P6 allele on the X chromosome. Control crosses of females carrying brn^1.6P6 with yellow white males did not yield any living brn^1.6P6 forked/Y males either. The inability of human 3GnT enzymes to compensate for the loss of brn activity in mutant flies suggested that the former enzymes cannot elongate the arthro-series glycolipid core in vivo. This was confirmed in vitro by showing that the human 3GnT enzymes did not exhibit significant activity toward the Man(1,4)Glc(1-OpNP) acceptor (Table II).

View this table: [in this window] [in a new window]   Table II Complementation of Drosophila brn1.6P6 Rescue of the brn1.6P6 late pupal lethal phenotype by ubiquitous expression of Drosophila brn and human 1,3GlcNAcT transgenes.

	DISCUSSION

TOP ABSTRACT INTRODUCTION EXPERIMENTAL PROCEDURES RESULTS DISCUSSION REFERENCES

We have shown that Drosophila brn, a member of the 1,3 glycosyltransferase family, encodes a 1,3 GlcNAcT enzyme with a specificity for the Man(1,4)Glc disaccharide found in arthro-series glycolipids (29). Several mammalian enzymes structurally related to brn have been suggested to represent homologues (35-37). However, the specificity of brn for Man(1,4)Glc, a disaccharide that has never been described in vertebrates, rather indicates that brn and mammalian 1,3 glycosyltransferases are paralogous proteins derived from a common ancestor gene.

The functional disparity between the 1,3 GlcNAcT brn and mammalian 1,3 GlcNAcT enzymes is further supported by the inability of the latter to complement the lethal phenotype of the mutant allele brn^1.6P6 in Drosophila. The specificity of brn toward Man1,4Glc-Cer suggests the presence of functional homologues only in organisms harboring arthro-series glycolipids, whose core structure is GlcNAc(1,3)Man(1,4)Glc-Cer. A protein structurally related to brn has recently been described in C. elegans (38), which express arthro-series glycolipids (28). The loss of that gene, named bre-5 (39), renders the animal resistant to high doses of Bacillus thuringiensis Bt toxin. Since Bt toxin binds to arthro-series glycolipids (40), it is possible that bre-5 participates in the formation of this class of glycolipids in C. elegans and thereby represents a true orthologue of brn.

brn mutations affect follicle cell-germ line interactions and lead to neurogenic phenotypes in Drosophila embryos. Considering the involvement of brn in glycolipid biosynthesis, one can envision that arthro-series glycolipids may regulate cell adhesion, proliferation, and differentiation via carbohydrate-lectin interactions. On the other hand, arthro-series glycolipids may modulate specific signaling proteins in a way similar to gangliosides affecting the epidermal growth factor receptor (41, 42), insulin receptor (43), and platelet-derived growth factor receptor (44) signaling cascades. The notion that brn glycolipid products interact with adhesion or signaling proteins implies that other mutant genes with phenotypes similar to those encountered in brn mutant flies may encode partner lectin/signaling proteins. Along this line, Drosophila egghead mutants have similar and non-additive phenotypes to brn (17). Experiments aimed at characterizing the biochemical and functional relation between brn products and the egghead protein should reveal the mechanisms how arthro-series glycolipids regulate morphogenic events during Drosophila development.

	ACKNOWLEDGEMENTS

We thank Erich Frei, Michael Daube, and Markus Noll from the Institute of Molecular Biology at the University of Zürich for their assistance with the transgenic expression in Drosophila.

	FOOTNOTES

^* This work was supported by Swiss National Science Foundation Grant 631-062662.00 (to T. H.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

^§ Present address: Dept. of Molecular Biology, Princeton University, Washington Rd., Princeton, NJ 08544-1014.

^¶ To whom correspondence should be addressed: Inst. of Physiology, Winterthurerstrasse 190, 8057 Zurich, Switzerland. Tel.: 41-1-635-5080; Fax: 41-1-635-6814; E-mail: thennet@access.unizh.ch.

Published, JBC Papers in Press, July 18, 2002, DOI 10.1074/jbc.C200381200

	ABBREVIATIONS

The abbreviations used are: GlcNAcT, N-acetylglucosaminyltransferase; brn, brainiac; TLC, thin-layer chromatography; pNP, p-nitrophenyl; Cer, ceramide; Lc2, Gal(1,4)Glc-Cer; Lc3, GlcNAc(1,3)Gal(1,4)Glc-Cer; HPLC, high performance liquid chromatography.

	REFERENCES

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This Article Abstract Full Text (PDF) All Versions of this Article: 277/36/32417    most recent C200381200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Müller, R. Articles by Hennet, T. Search for Related Content PubMed PubMed Citation Articles by Müller, R. Articles by Hennet, T. Social Bookmarking                      What's this?